NM_000044.6(AR):c.2186T>C (p.Leu729Ser) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 22, 2023
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:: RCV003783772.2

Allele description [Variation Report for NM_000044.6(AR):c.2186T>C (p.Leu729Ser)]

NM_000044.6(AR):c.2186T>C (p.Leu729Ser)

Gene:

AR:androgen receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq12

Genomic location:

Preferred name:

NM_000044.6(AR):c.2186T>C (p.Leu729Ser)

HGVS:

NC_000023.11:g.67717490T>C
NG_009014.2:g.178459T>C
NM_000044.6:c.2186T>CMANE SELECT
NM_001011645.3:c.590T>C
NM_001424175.1:c.2189T>C
NP_000035.2:p.Leu729Ser
NP_001011645.1:p.Leu197Ser
NP_001411104.1:p.Leu730Ser
LRG_1406t1:c.2186T>C
LRG_1406:g.178459T>C
LRG_1406p1:p.Leu729Ser
NC_000023.10:g.66937332T>C

Protein change:

L197S

Molecular consequence:

NM_000044.6:c.2186T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001011645.3:c.590T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001424175.1:c.2189T>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
SCV004571478	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1430233, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004571478

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 22, 2023)

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

Mutations in the ligand-binding domain of the androgen receptor gene cluster in two regions of the gene.

McPhaul MJ, Marcelli M, Zoppi S, Wilson CM, Griffin JE, Wilson JD.

J Clin Invest. 1992 Nov;90(5):2097-101.

PubMed [citation]

PMID:: 1430233
PMCID:: PMC443277

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, SCV004571478.1

#	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 leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 729 of the AR protein (p.Leu729Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of AR-related conditions (PMID: 1430233). This variant is also known as L726S. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AR protein function. 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.

#	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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