NM_001128178.3(NPHP1):c.1009A>C (p.Met337Leu) AND Nephronophthisis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 26, 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:: RCV001338575.7

Allele description [Variation Report for NM_001128178.3(NPHP1):c.1009A>C (p.Met337Leu)]

NM_001128178.3(NPHP1):c.1009A>C (p.Met337Leu)

Gene:

NPHP1:nephrocystin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q13

Genomic location:

Preferred name:

NM_001128178.3(NPHP1):c.1009A>C (p.Met337Leu)

HGVS:

NC_000002.12:g.110160201T>G
NG_008287.1:g.49862A>C
NM_000272.3:c.1177A>C
NM_000272.5:c.1177A>C
NM_001128178.3:c.1009A>CMANE SELECT
NM_001128179.3:c.820A>C
NM_001374256.1:c.1006A>C
NM_001374257.1:c.1009A>C
NM_207181.4:c.1174A>C
NP_000263.2:p.Met393Leu
NP_001121650.1:p.Met337Leu
NP_001121651.1:p.Met274Leu
NP_001361185.1:p.Met336Leu
NP_001361186.1:p.Met337Leu
NP_997064.2:p.Met392Leu
NC_000002.11:g.110917778T>G
NM_000272.4:c.1177A>C

Protein change:

M274L

Links:

dbSNP: rs780706360

NCBI 1000 Genomes Browser:

rs780706360

Molecular consequence:

NM_000272.5:c.1177A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128178.3:c.1009A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128179.3:c.820A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374256.1:c.1006A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374257.1:c.1009A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_207181.4:c.1174A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Nephronophthisis
Synonyms:: juvenile nephronophthisis
Identifiers:: MONDO: MONDO:0019005; MedGen: C0687120; OMIM: PS256100; Human Phenotype Ontology: HP:0000090

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001532255	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 26, 2021)	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

SCV001532255

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 26, 2021)

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, SCV001532255.4

#	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 methionine with leucine at codon 393 of the NPHP1 protein (p.Met393Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs780706360, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with NPHP1-related conditions. 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 tolerated. 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: Oct 8, 2024

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