NM_005585.5(SMAD6):c.2T>G (p.Met1Arg) AND Aortic valve disease 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 2, 2017
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:: RCV001322811.7

Allele description [Variation Report for NM_005585.5(SMAD6):c.2T>G (p.Met1Arg)]

NM_005585.5(SMAD6):c.2T>G (p.Met1Arg)

Gene:

SMAD6:SMAD family member 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q22.31

Genomic location:

Preferred name:

NM_005585.5(SMAD6):c.2T>G (p.Met1Arg)

HGVS:

NC_000015.10:g.66703260T>G
NG_012244.2:g.5925T>G
NM_005585.5:c.2T>GMANE SELECT
NP_005576.3:p.Met1Arg
NC_000015.9:g.66995598T>G
NG_012244.1:g.5925T>G
NM_005585.4:c.2T>G
NR_027654.2:n.1025T>G

Protein change:

M1R

Links:

dbSNP: rs1409145798

NCBI 1000 Genomes Browser:

rs1409145798

Molecular consequence:

NM_005585.5:c.2T>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_005585.5:c.2T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_027654.2:n.1025T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Aortic valve disease 2 (AOVD2)
Identifiers:: MONDO: MONDO:0013902; MedGen: C3542024; OMIM: 614823

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001513700	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 2, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001513700

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 2, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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, SCV001513700.5

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

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. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SMAD6 cause disease. This variant has not been reported in the literature in individuals with SMAD6-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change affects the initiator methionine of the SMAD6 mRNA. While it is expected to result in an absent or disrupted protein product an alternate in-frame methionine downstream of the original initiator codon located at codon 93 could potentially rescue translation initiation.

#	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: Oct 8, 2024

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