NM_133642.5(LARGE1):c.1420G>A (p.Val474Ile) AND Muscular dystrophy-dystroglycanopathy type B6

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000540677.21

Allele description [Variation Report for NM_133642.5(LARGE1):c.1420G>A (p.Val474Ile)]

NM_133642.5(LARGE1):c.1420G>A (p.Val474Ile)

Gene:

LARGE1:LARGE xylosyl- and glucuronyltransferase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.3

Genomic location:

Preferred name:

NM_133642.5(LARGE1):c.1420G>A (p.Val474Ile)

Other names:

p.V474I:GTC>ATC

HGVS:

NC_000022.11:g.33316116C>T
NG_009929.2:g.609313G>A
NM_001362949.2:c.1420G>A
NM_001362951.2:c.1420G>A
NM_001362953.2:c.1420G>A
NM_001378624.1:c.1420G>A
NM_001378625.1:c.1420G>A
NM_001378626.1:c.1420G>A
NM_001378627.1:c.1420G>A
NM_001378628.1:c.1420G>A
NM_001378629.1:c.1264G>A
NM_001378630.1:c.817G>A
NM_001378631.1:c.661G>A
NM_004737.5:c.1420G>A
NM_004737.7:c.1420G>A
NM_133642.5:c.1420G>AMANE SELECT
NP_001349878.1:p.Val474Ile
NP_001349880.1:p.Val474Ile
NP_001349882.1:p.Val474Ile
NP_001365553.1:p.Val474Ile
NP_001365554.1:p.Val474Ile
NP_001365555.1:p.Val474Ile
NP_001365556.1:p.Val474Ile
NP_001365557.1:p.Val474Ile
NP_001365558.1:p.Val422Ile
NP_001365559.1:p.Val273Ile
NP_001365560.1:p.Val221Ile
NP_004728.1:p.Val474Ile
NP_598397.1:p.Val474Ile
LRG_856t1:c.1420G>A
LRG_856t2:c.1420G>A
LRG_856:g.609313G>A
LRG_856p1:p.Val474Ile
LRG_856p2:p.Val474Ile
NC_000022.10:g.33712102C>T
NM_004737.4:c.1420G>A
NM_004737.6:c.1420G>A

Protein change:

V221I

Links:

dbSNP: rs150861748

NCBI 1000 Genomes Browser:

rs150861748

Molecular consequence:

NM_001362949.2:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001362951.2:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001362953.2:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378624.1:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378625.1:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378626.1:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378627.1:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378628.1:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378629.1:c.1264G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378630.1:c.817G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378631.1:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004737.7:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133642.5:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Muscular dystrophy-dystroglycanopathy type B6 (MDDGB6)
Synonyms:: MUSCULAR DYSTROPHY, CONGENITAL, LARGE-RELATED; MUSCULAR DYSTROPHY, CONGENITAL, TYPE 1D; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 6
Identifiers:: MONDO: MONDO:0012138; MedGen: C1837229; OMIM: 608840

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000638975	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 22, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001309188	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000638975

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 22, 2024)

germline

clinical testing

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

SCV001309188

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

Citation Link

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000638975.9

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

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 474 of the LARGE1 protein (p.Val474Ile). This variant is present in population databases (rs150861748, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LARGE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 95164). 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) performed at Invitae indicates that this missense variant is not expected to disrupt LARGE1 protein function with a negative predictive value of 80%. 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

From Illumina Laboratory Services, Illumina, SCV001309188.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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: Apr 15, 2024

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