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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 20, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001255223.2

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:: Oligospermia
Identifiers:: MONDO: MONDO:0001913; MeSH: D009845; MedGen: C0028960

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001169709	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

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001169709

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]

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

Citations

PubMed

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

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

Details of each submission

From Clinical Bioinformatic Lab, Royan Institute, SCV001169709.1

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

Description

A consanguineous family with 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.

Description

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.

#	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

Last Updated: Sep 8, 2024

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