NM_017777.4(MKS1):c.958G>A (p.Val320Ile) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 2, 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:: RCV001853066.5

Allele description [Variation Report for NM_017777.4(MKS1):c.958G>A (p.Val320Ile)]

NM_017777.4(MKS1):c.958G>A (p.Val320Ile)

Gene:

MKS1:MKS transition zone complex subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q22

Genomic location:

Preferred name:

NM_017777.4(MKS1):c.958G>A (p.Val320Ile)

HGVS:

NC_000017.11:g.58210980C>T
NG_013032.1:g.13626G>A
NM_001321268.2:c.349G>A
NM_001321269.2:c.958G>A
NM_001330397.2:c.958G>A
NM_017777.4:c.958G>AMANE SELECT
NP_001308197.1:p.Val117Ile
NP_001308198.1:p.Val320Ile
NP_001317326.1:p.Val320Ile
NP_060247.2:p.Val320Ile
NP_060247.2:p.Val320Ile
LRG_687t1:c.958G>A
LRG_687:g.13626G>A
LRG_687p1:p.Val320Ile
NC_000017.10:g.56288341C>T
NM_017777.3:c.958G>A

Protein change:

V117I

Links:

dbSNP: rs386834053

NCBI 1000 Genomes Browser:

rs386834053

Molecular consequence:

NM_001321268.2:c.349G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321269.2:c.958G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330397.2:c.958G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_017777.4:c.958G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial aplasia of the vermis
Synonyms:: CEREBELLOPARENCHYMAL DISORDER IV; Joubert syndrome; Cerebelloparenchymal disorder 4; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300

Name:: Meckel-Gruber syndrome
Synonyms:: DYSENCEPHALIA SPLANCHNOCYSTICA; Gruber syndrome; Dysencephalia splachnocystica
Identifiers:: MONDO: MONDO:0018921; MedGen: C0265215; OMIM: PS249000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002268178	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 2, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17397051, 31191208, 35587316, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002268178

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 2, 2023)

germline

clinical testing

PubMed (6)
[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

Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online.

Khaddour R, Smith U, Baala L, Martinovic J, Clavering D, Shaffiq R, Ozilou C, Cullinane A, Kyttälä M, Shalev S, Audollent S, d'Humières C, Kadhom N, Esculpavit C, Viot G, Boone C, Oien C, Encha-Razavi F, Batman PA, Bennett CP, Woods CG, Roume J, et al.

Hum Mutat. 2007 May;28(5):523-4.

PubMed [citation]

PMID:: 17397051

Co-Occurrence of Leber Congenital Amaurosis and Meckel Syndrome Type 1 in a Fetus: Is There a Lesson to Be Learned?

Tallapaka K, Aggarwal S, Bhattacherjee A, Das Bhowmik A, Dalal A.

Mol Syndromol. 2019 May;10(3):177-182. doi: 10.1159/000496280. Epub 2019 Jan 22.

PubMed [citation]

PMID:: 31191208
PMCID:: PMC6528073

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002268178.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects codon 320 of the MKS1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MKS1 protein. This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is present in population databases (rs386834053, gnomAD 0.005%). This variant has been observed in individual(s) with MKS1-related conditions (PMID: 17397051, 31191208, 35587316). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56627). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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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