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NM_002334.4(LRP4):c.3830G>A (p.Arg1277His) AND multiple conditions

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 28, 2021
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:
RCV000691410.5

Allele description [Variation Report for NM_002334.4(LRP4):c.3830G>A (p.Arg1277His)]

NM_002334.4(LRP4):c.3830G>A (p.Arg1277His)

Gene:
LRP4:LDL receptor related protein 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p11.2
Genomic location:
Preferred name:
NM_002334.4(LRP4):c.3830G>A (p.Arg1277His)
HGVS:
  • NC_000011.10:g.46875551C>T
  • NG_021394.1:g.48072G>A
  • NM_002334.4:c.3830G>AMANE SELECT
  • NP_002325.2:p.Arg1277His
  • NC_000011.9:g.46897102C>T
  • NM_002334.3:c.3830G>A
  • O75096:p.Arg1277His
Protein change:
R1277H; ARG1277HIS
Links:
UniProtKB: O75096#VAR_073696; OMIM: 604270.0012; dbSNP: rs746136135
NCBI 1000 Genomes Browser:
rs746136135
Molecular consequence:
  • NM_002334.4:c.3830G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cenani-Lenz syndactyly syndrome
Synonyms:
SYNDACTYLY, TYPE VII; Syndactyly Cenani Lenz type; Cenani syndactylism; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008931; MedGen: C1859309; Orphanet: 3258; OMIM: 212780
Name:
Sclerosteosis 2 (SOST2)
Identifiers:
MONDO: MONDO:0013679; MedGen: C3280402; Orphanet: 3152; OMIM: 614305
Name:
Congenital myasthenic syndrome 17
Identifiers:
MONDO: MONDO:0014578; MedGen: C4225377; Orphanet: 590; OMIM: 616304

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000819188Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Aug 28, 2021)
germlineclinical testing

PubMed (2)
[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

LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner.

Ohkawara B, Cabrera-Serrano M, Nakata T, Milone M, Asai N, Ito K, Ito M, Masuda A, Ito Y, Engel AG, Ohno K.

Hum Mol Genet. 2014 Apr 1;23(7):1856-68. doi: 10.1093/hmg/ddt578. Epub 2013 Nov 13.

PubMed [citation]
PMID:
24234652
PMCID:
PMC3943522

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 Invitae, SCV000819188.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine with histidine at codon 1277 of the LRP4 protein (p.Arg1277His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs746136135, ExAC 0.006%). This missense change has been observed in individual(s) with clinical features of congenital myasthenic syndrome (PMID: 24234652). ClinVar contains an entry for this variant (Variation ID: 189821). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects LRP4 function (PMID: 24234652). 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.

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

Last Updated: Feb 7, 2023