NM_000044.6(AR):c.1844G>C (p.Cys615Ser) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 6, 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:: RCV000809289.8

Allele description [Variation Report for NM_000044.6(AR):c.1844G>C (p.Cys615Ser)]

NM_000044.6(AR):c.1844G>C (p.Cys615Ser)

Gene:

AR:androgen receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq12

Genomic location:

Preferred name:

NM_000044.6(AR):c.1844G>C (p.Cys615Ser)

HGVS:

NC_000023.11:g.67686085G>C
NG_009014.2:g.147054G>C
NM_000044.6:c.1844G>CMANE SELECT
NM_001011645.3:c.248G>C
NM_001348061.1:c.1844G>C
NM_001348063.1:c.1844G>C
NM_001348064.1:c.*42G>C
NP_000035.2:p.Cys615Ser
NP_001011645.1:p.Cys83Ser
NP_001334990.1:p.Cys615Ser
NP_001334992.1:p.Cys615Ser
LRG_1406t1:c.1844G>C
LRG_1406:g.147054G>C
LRG_1406p1:p.Cys615Ser
NC_000023.10:g.66905927G>C
NM_000044.3:c.1844G>C

Protein change:

C615S

Links:

dbSNP: rs1602255415

NCBI 1000 Genomes Browser:

rs1602255415

Molecular consequence:

NM_001348064.1:c.*42G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000044.6:c.1844G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001011645.3:c.248G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001348061.1:c.1844G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001348063.1:c.1844G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Androgen resistance syndrome (AIS)
Synonyms:: TESTICULAR FEMINIZATION SYNDROME; Androgen insensitivity syndrome; Androgen receptor deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0019154; MedGen: C0039585; Orphanet: 99429; OMIM: 300068

Name:: Kennedy disease (SMAX1)
Synonyms:: SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1; Bulbo-spinal atrophy X-linked; Kennedy spinal and bulbar muscular atrophy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010735; MedGen: C1839259; Orphanet: 481; OMIM: 313200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000949435	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 6, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15925895, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000949435

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 6, 2019)

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

Novel and recurrent mutations in patients with androgen insensitivity syndromes.

Ledig S, Jakubiczka S, Neulen J, Aulepp U, Burck-Lehmann U, Mohnike K, Thiele H, Zierler H, Brewer C, Wieacker P.

Horm Res. 2005;63(6):263-9. Epub 2005 May 26.

PubMed [citation]

PMID:: 15925895

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, SCV000949435.6

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

Description

This sequence change replaces cysteine with serine at codon 615 of the AR protein (p.Cys615Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). 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.Cys615 amino acid residue in AR. Other variant(s) that disrupt this residue have been observed in individuals with AR-related conditions (PMID: 15925895, also known as p.Cys614Tyr), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with AR-related conditions.

#	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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