NM_003140.3(SRY):c.226C>T (p.Arg76Cys) AND 46,XY sex reversal 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 1, 2020
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:: RCV002001650.6

Allele description [Variation Report for NM_003140.3(SRY):c.226C>T (p.Arg76Cys)]

NM_003140.3(SRY):c.226C>T (p.Arg76Cys)

Gene:

SRY:sex determining region Y [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Yp11.2

Genomic location:

Preferred name:

NM_003140.3(SRY):c.226C>T (p.Arg76Cys)

HGVS:

NC_000024.10:g.2787378G>A
NG_011751.1:g.5374C>T
NM_003140.3:c.226C>TMANE SELECT
NP_003131.1:p.Arg76Cys
NC_000024.9:g.2655419G>A

Protein change:

R76C

Links:

dbSNP: rs2124486234

NCBI 1000 Genomes Browser:

rs2124486234

Molecular consequence:

NM_003140.3:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: 46,XY sex reversal 1
Synonyms:: 46,XY SEX REVERSAL, SRY-RELATED; SRY-related 46,XY complete gonadal dysgenesis
Identifiers:: MONDO: MONDO:0020712; MedGen: C2748896; Orphanet: 242; OMIM: 400044

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002276505	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 1, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10670762, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002276505

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 1, 2020)

germline

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel sex-determining region on Y (SRY) missense mutation identified in a 46,XY female and also in the father.

Imai A, Takagi A, Tamaya T.

Endocr J. 1999 Oct;46(5):735-9.

PubMed [citation]

PMID:: 10670762

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002276505.3

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg76 amino acid residue in SRY. Other variant(s) that disrupt this residue have been observed in individuals with SRY-related conditions (PMID: 10670762, Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of 46XY sex reversal (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 76 of the SRY protein (p.Arg76Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine.

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

Last Updated: Sep 29, 2024

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