NM_002440.4(MSH4):c.2261C>T (p.Ser754Leu) AND Non-obstructive azoospermia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 24, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001255224.6

Allele description [Variation Report for NM_002440.4(MSH4):c.2261C>T (p.Ser754Leu)]

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

Gene:

MSH4:mutS homolog 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

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

Other names:

MSH4, SER754LEU (rs377712900)

HGVS:

NC_000001.11:g.75890730C>T
NG_029861.1:g.98860C>T
NM_002440.4:c.2261C>TMANE SELECT
NP_002431.2:p.Ser754Leu
NC_000001.10:g.76356415C>T

Protein change:

S754L; SER754LEU

Links:

OMIM: 602105.0003; dbSNP: rs377712900

NCBI 1000 Genomes Browser:

rs377712900

Molecular consequence:

NM_002440.4:c.2261C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

variation affecting protein function [Variation Ontology: 0003]

Observations:

Condition(s)

Name:: Non-obstructive azoospermia
Identifiers:: MedGen: C4021107; Human Phenotype Ontology: HP:0011961

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001169708	Clinical Bioinformatic Lab, Royan Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 20, 2019)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 33448284
SCV001468894	Institute of Reproductive Genetics, University of Münster	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2021)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001169708

Clinical Bioinformatic Lab, Royan Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 20, 2019)

inherited

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001468894

Institute of Reproductive Genetics, University of Münster

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 24, 2021)

germline

research

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
Caucasian	inherited	yes	5	1	not provided	not provided	not provided	clinical testing
non-Finnish European	germline	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals.

Akbari A, Padidar K, Salehi N, Mashayekhi M, Almadani N, Sadighi Gilani MA, Bashambou A, McElreavey K, Totonchi M.

Hum Reprod. 2021 Mar 18;36(4):1134-1145. doi: 10.1093/humrep/deaa362.

PubMed [citation]

PMID:: 33448284

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Clinical Bioinformatic Lab, Royan Institute, SCV001169708.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	5	not provided	not provided	clinical testing	PubMed (2)

Description

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.

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		5	not provided	1	not provided

From Institute of Reproductive Genetics, University of Münster, SCV001468894.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	non-Finnish European	1	not provided	not provided	research	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 8, 2024

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