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NM_003140.3(SRY):c.380A>G (p.Tyr127Cys) AND 46,XY sex reversal 1

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 25, 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:
RCV000541250.12

Allele description [Variation Report for NM_003140.3(SRY):c.380A>G (p.Tyr127Cys)]

NM_003140.3(SRY):c.380A>G (p.Tyr127Cys)

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.380A>G (p.Tyr127Cys)
HGVS:
  • NC_000024.10:g.2787224T>C
  • NG_011751.1:g.5528A>G
  • NM_003140.3:c.380A>GMANE SELECT
  • NP_003131.1:p.Tyr127Cys
  • NC_000024.9:g.2655265T>C
  • NM_003140.2:c.380A>G
Protein change:
Y127C
Links:
dbSNP: rs104894973
NCBI 1000 Genomes Browser:
rs104894973
Molecular consequence:
  • NM_003140.3:c.380A>G - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000647883Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 25, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father.

Jordan BK, Jain M, Natarajan S, Frasier SD, Vilain E.

J Clin Endocrinol Metab. 2002 Jul;87(7):3428-32.

PubMed [citation]
PMID:
12107262

Functional Analysis of Mutations at Codon 127 of the SRY Gene Associated with 46,XY Complete Gonadal Dysgenesis.

Tajouri A, Ben Gaied D, Hizem S, Boujelben S, Maazoul F, M'rad R, Poulat F, Kharrat M.

Sex Dev. 2017;11(4):203-209. doi: 10.1159/000478718. Epub 2017 Aug 9.

PubMed [citation]
PMID:
28787711
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000647883.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the p.Tyr127 amino acid residue in SRY have been observed in affected individuals (PMID: 12107262, 28787711). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change disrupts the ability of SRY to accumulate in the nucleus and bind to DNA in cell culture, but does not affect its interaction with calmodulin (PMID: 12409269, 20528776). This variant has been observed to be de novo in an individual affected with 46,XY disorder of sexual development (46,XY DSD) (Invitae) and has also been reported in the literature in an additional individual affected with 46, XY DSD (PMID: 8019555). ClinVar contains an entry for this variant (Variation ID: 470196). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 127 of the SRY protein (p.Tyr127Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024