VCV000869115.6 - ClinVar

NM_002440.4(MSH4):c.2261C>T (p.Ser754Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002440.4(MSH4):c.2261C>T (p.Ser754Leu)

Variation ID: 869115 Accession: VCV000869115.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.1 1: 75890730 (GRCh38) [ NCBI UCSC ] 1: 76356415 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 16, 2020	Jul 8, 2022	May 24, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_002440.4:c.2261C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002431.2:p.Ser754Leu	missense
NC_000001.11:g.75890730C>T
NC_000001.10:g.76356415C>T
NG_029861.1:g.98860C>T

Protein change

S754L

Other names

MSH4, SER754LEU (rs377712900)

Canonical SPDI

NC_000001.11:75890729:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

variation affecting protein function; Variation Ontology [ VariO:0003]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

The Genome Aggregation Database (gnomAD) 0.00005

Exome Aggregation Consortium (ExAC) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

OMIM: 602105.0003 dbSNP: rs377712900 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MSH4		-	-	GRCh38 GRCh37	97	122

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Premature ovarian insufficiency	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2019	RCV001201398.2
Oligospermia	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2019	RCV001255223.2
Non-obstructive azoospermia	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 24, 2021	RCV001255224.6
Spermatogenic failure 2	Pathogenic (1)	no assertion criteria provided	Jul 1, 2022	RCV002260683.2
Premature ovarian failure 20	Pathogenic (1)	no assertion criteria provided	Jul 1, 2022	RCV002260684.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Premature ovarian insufficiency (Autosomal recessive inheritance) Affected status: no, yes Allele origin: inherited	Clinical Bioinformatic Lab, Royan Institute Accession: SCV001142647.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020	Publications: PubMed (1) PubMed: 33448284 Comment: Knockout mouse models of MSH4 have been reported to be infertile in both genders due to meiotic arrest (Kneitz, 2000). In human an MSH4 splice … (more) Knockout mouse models of MSH4 have been reported to be infertile in both genders due to meiotic arrest (Kneitz, 2000). In human an MSH4 splice site variant has been reported to cause premature ovarian failure (Carlosama, 2017). Exon 17 of this gene encodes a number of functional domains and is highly conserved. Here, we report the S754L variant in exon 17 as the genetic cause of azoospermia and premature ovarian failure in homozygous state and oligozoospermia in the heterozygous state in a consanguineous family. (less) Observation 1: Number of individuals with the variant: 5 Number of families with the variant: 1 Zygosity: Homozygote, Compound Heterozygote, Hemizygote Age: 25-45 years Sex: mixed Ethnicity/Population group: Caucasian Geographic origin: Iran Comment on evidence: A consanguineous family with POI, AZ and oligozoospermia was recruited for WES having been clinically investigated according to ESHRE and ASRM respective guidelines. POI and … (more) A consanguineous family with POI, AZ and oligozoospermia was recruited for WES having been clinically investigated according to ESHRE and ASRM respective guidelines. POI and AZ patients were found to be homozygous for a rare MSH4 variant while their oligozoospermic sibling was heterozygous. Out of 5 total homozygous patients for the variant, 2 were females with POI (less) Observation 2: Number of individuals with the variant: 5 Zygosity: Single Heterozygote Ethnicity/Population group: Caucasian Geographic origin: Iran Comment on evidence: Heterozygotic siblings with this MSH4 variant are oligozoospermic.
Pathogenic (Mar 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Non-obstructive azoospermia (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Clinical Bioinformatic Lab, Royan Institute Accession: SCV001169708.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Publications: PubMed (1) PubMed: 33448284 Comment: Knockout mouse models of MSH4 have been reported to be infertile in both genders due to meiotic arrest (Kneitz, 2000). Exon 17 of this gene … (more) Knockout mouse models of MSH4 have been reported to be infertile in both genders due to meiotic arrest (Kneitz, 2000). Exon 17 of this gene encodes a number of functional domains and is highly conserved. Here, we report the S754L variant in exon 17 as the genetic cause of non-obstructive azoospermia in homozygous state in a consanguineous family. (less) Number of individuals with the variant: 5 Zygosity: Homozygote Age: 25-45 years Sex: mixed Ethnicity/Population group: Caucasian Geographic origin: Iran Comment on evidence: A consanguineous family with non-obstructive azoospermia was recruited for WES having been clinically investigated according to ASRM guideline. Patients were found to be homozygous for … (more) A consanguineous family with non-obstructive azoospermia was recruited for WES having been clinically investigated according to ASRM guideline. Patients were found to be homozygous for a rare MSH4 variant. (less)
Pathogenic (Mar 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Oligospermia (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Clinical Bioinformatic Lab, Royan Institute Accession: SCV001169709.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Publications: PubMed (1) PubMed: 33448284 Comment: Knockout mouse models of MSH4 have been reported to be infertile in both genders due to meiotic arrest (Kneitz, 2000). In human an MSH4 splice … (more) Knockout mouse models of MSH4 have been reported to be infertile in both genders due to meiotic arrest (Kneitz, 2000). In human an MSH4 splice site variant has been reported to cause premature ovarian failure (Carlosama, 2017). Exon 17 of this gene encodes a number of functional domains and is highly conserved. Here, we report the S754L variant in exon 17 as the genetic cause of azoospermia and premature ovarian failure in homozygous state and oligozoospermia in the heterozygous state in a consanguineous family. (less) Number of individuals with the variant: 5 Zygosity: Single Heterozygote Age: 25-45 years Sex: male Ethnicity/Population group: Caucasian Geographic origin: Iran Comment on evidence: A consanguineous family with POI, AZ and oligozoospermia was recruited for WES having been clinically investigated according to ESHRE and ASRM respective guidelines. POI and … (more) A consanguineous family with POI, AZ and oligozoospermia was recruited for WES having been clinically investigated according to ESHRE and ASRM respective guidelines. POI and AZ patients were found to be homozygous for a rare MSH4 variant while their only oligozoospermic sibling was heterozygous. (less)
Likely pathogenic (May 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Non-obstructive azoospermia (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Reproductive Genetics, University of Münster Accession: SCV001468894.2 First in ClinVar: Jan 17, 2021 Last updated: May 27, 2021	Comment: Currently this variant was described in a woman with premature ovarian insufficiency and an additional man with non-obstructive azoospermia, strengthening evidence for the pathogenicity of … (more) Currently this variant was described in a woman with premature ovarian insufficiency and an additional man with non-obstructive azoospermia, strengthening evidence for the pathogenicity of this variant in context of infertility (Akbari et al, 2021). (less) Number of individuals with the variant: 1 Age: 30-50 years Sex: male Ethnicity/Population group: non-Finnish European
Pathogenic (Jul 01, 2022)	no assertion criteria provided Method: literature only	SPERMATOGENIC FAILURE 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV002540598.1 First in ClinVar: Jul 08, 2022 Last updated: Jul 08, 2022	Publications: PubMed (1) PubMed: 33448284 Comment on evidence: In a consanguineous Iranian family with both male infertility due to azoospermia (SPGF2; 108420), and female infertility due to premature ovarian failure (POF20; 619938), Akbari … (more) In a consanguineous Iranian family with both male infertility due to azoospermia (SPGF2; 108420), and female infertility due to premature ovarian failure (POF20; 619938), Akbari et al. (2021) identified homozygosity for a c.2261C-T transition (c.2261C-T, NM_002440.4) in exon 17 of the MSH4 gene, resulting in a ser754-to-leu (S754L) substitution at a highly conserved residue initiating the signature motif of MutS domain V. Five infertile sibs were homozygous for the variant, including 2 sisters with POF and 3 brothers with azoospermia. Sanger sequencing confirmed the mutation and its presence in heterozygosity in the first-cousin parents and 3 fertile sisters, as well as in an infertile brother with oligozoospermia. The variant was found at low minor allele frequency (0.0001) in the gnomAD database, but never in homozygosity. (less)
Pathogenic (Jul 01, 2022)	no assertion criteria provided Method: literature only	PREMATURE OVARIAN FAILURE 20 Affected status: not provided Allele origin: germline	OMIM Accession: SCV002540599.1 First in ClinVar: Jul 08, 2022 Last updated: Jul 08, 2022	Publications: PubMed (1) PubMed: 33448284 Comment on evidence: In a consanguineous Iranian family with both male infertility due to azoospermia (SPGF2; 108420), and female infertility due to premature ovarian failure (POF20; 619938), Akbari … (more) In a consanguineous Iranian family with both male infertility due to azoospermia (SPGF2; 108420), and female infertility due to premature ovarian failure (POF20; 619938), Akbari et al. (2021) identified homozygosity for a c.2261C-T transition (c.2261C-T, NM_002440.4) in exon 17 of the MSH4 gene, resulting in a ser754-to-leu (S754L) substitution at a highly conserved residue initiating the signature motif of MutS domain V. Five infertile sibs were homozygous for the variant, including 2 sisters with POF and 3 brothers with azoospermia. Sanger sequencing confirmed the mutation and its presence in heterozygosity in the first-cousin parents and 3 fertile sisters, as well as in an infertile brother with oligozoospermia. The variant was found at low minor allele frequency (0.0001) in the gnomAD database, but never in homozygosity. (less)

Comment:

Knockout mouse models of MSH4 have been reported to be infertile in both genders due to meiotic arrest (Kneitz, 2000). In human an MSH4 splice site variant has been reported to cause premature ovarian failure (Carlosama, 2017). Exon 17 of this gene encodes a number of functional domains and is highly conserved. Here, we report the S754L variant in exon 17 as the genetic cause of azoospermia and premature ovarian failure in homozygous state and oligozoospermia in the heterozygous state in a consanguineous family.

Comment:

Knockout mouse models of MSH4 have been reported to be infertile in both genders due to meiotic arrest (Kneitz, 2000). Exon 17 of this gene encodes a number of functional domains and is highly conserved. Here, we report the S754L variant in exon 17 as the genetic cause of non-obstructive azoospermia in homozygous state in a consanguineous family.

Comment:

Currently this variant was described in a woman with premature ovarian insufficiency and an additional man with non-obstructive azoospermia, strengthening evidence for the pathogenicity of this variant in context of infertility (Akbari et al, 2021).

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
variation affecting protein function (VariO:0003)	Clinical Bioinformatic Lab, Royan Institute Accession: SCV001142647.1	Publications PubMed (1)
variation affecting protein function (VariO:0003)	Clinical Bioinformatic Lab, Royan Institute Accession: SCV001169708.1	Publications PubMed (1)
variation affecting protein function (VariO:0003)	Clinical Bioinformatic Lab, Royan Institute Accession: SCV001169709.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals.	Akbari A	Human reproduction (Oxford, England)	2021	PMID: 33448284

Text-mined citations for rs377712900 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 08, 2024

ClinVar Genomic variation as it relates to human health

NM_002440.4(MSH4):c.2261C>T (p.Ser754Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377712900 ...